HRP20040747A2 - Powder inhalation containing cgrp-antagonist bibn4096 and method for the production therof - Google Patents

Description

The invention relates to an inhalation powder containing the CGRP antagonist 1-[N2-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxo-quinazolin-3-yl)-1 -piperidinyl]carbonyl]-D-tyrosyl]-1-lysyl]-4-(4-pyridinyl)-piperazine [BIBN4096] of formula I in the form of round nanostructured microparticles, which under normal conditions (T <50ºC, relative humidity <75 %) present in their stable amorphous state, as well as the process for their production, by which the thermodynamically stable, i.e. stabilized active substance in the amorphous state can be processed into microparticles in a single step.

The round nanostructured microparticles according to the invention are suitable for the production of inhalable powders, where no further excipient or additional substance (carrier materials) is required to obtain a powder that can be handled technically, can be directly further processed and has excellent properties in terms of dispersibility and in terms of its cohesive properties, and which are sufficient for it to be well processed, A further aspect of the invention is a powder for inhalation which can be obtained by the process according to the invention. Formula I:

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State of the art

BIBN4096 represents a highly effective CGRP antagonist for the treatment of migraine, the application of which is not possible orally using classical administration forms, because this substance has a very limited oral bioavailability.

In case of application in the form of inhalation powder, which is filled in suitable capsules (inhalates), it is brought to the lungs using a powder inhaler. Alternatively, the inhalation application can also be carried out by the application of a suitable powder inhalation aerosol, which contains, for example, HFA134a, HFA227 or a mixture thereof as a propellant gas.

At the same time, microparticles of the pure active substance are applied through the respiratory tract to the surface of the lungs, for example in the alveoli, by inhalation. These particles are deposited on the surface and only after dissolution can the body take them up through active and passive transport processes.

Inhalation systems are known in the literature in which the active substance is present as a micronized suspension in a suitable solvent system as a carrier or in the form of a dry powder.

The inhalation powder is usually produced, for example, in the form of capsules for inhalation based on the general instruction described in DE-A-179 22 07, using a chemically stable form of the active substance. In doing so, pharmaceutical preparations, produced by mixing finely divided medicine with coarser carrier particles, are dispersed in the air stream using the so-called "powder flow process" using the suction function of the inhaler as the main energy source.

A critical factor in such multi-substance systems is the uniform distribution of the drug in the powder mixture. Furthermore, the additional burden on the lungs is caused by the carrier, as well as the occurrence of unwanted interactions, which can lead to compatibility problems.

A significant aspect of the inhalation application of the active substance is that only particles of a certain aerodynamic size reach the target organ, the lungs. The size of these particles that reach the lungs (the fraction that can be inhaled) is in the sub-micron range. Such particles are usually obtained by micronization (grinding with an air current). It often follows that such particles, with this mechanical step, in terms of their crystal properties, can have a complex composition. Also, the geometric shape of the particles of the starting material determines the morphological properties of the micronisate.

In addition to the jet milling process, in which the jet milling process is of particular importance, suitable micronises can also be produced by alternative processes. Suitable micronization processes for the production of microparticles in the sub-micron range are, for example, a deposition process, including a process by which the active substance can be precipitated as a non-crystalline solid (amorphous) by concentrating the solvent below the maximum solubility, deposition using supercritical gases, such as RESS - or PGSS-procedure (J. Jung, M. Perrut: Particle Design Using Supercritical Fluids, J. Supercrit. Fluids 20 (2001), 179-219), GASR procedure (M.P. Gallager et al.: Gas Antisolvent Recrystallization, Am. Chem. Soc. (1989) ), PCA procedure (D.J. Dixon, K.P. Johnston: Polymeric Materials Formed by Precipitation with compressed Fluid Antisolvent, AIChE Journal (1993, Vol. 39 (1), 127), freeze drying, spray drying or a combination more of the above procedures.

It is known from the literature that spray drying can produce particles that reach the lungs and have a size between 0.5 μm and 10 μm, preferably between 0.5 μm and 6 μm. Formulations are usually produced from such particles, obtained by spray drying, based on the process cited above (DE-A-179 22 07), which can be handled technically and which have sufficient dispersibility for medical use (inhalation) [Y.- F. Maa, P.-A. Mgyuyen, J.D. Andya, N. Dasovich, T.D. Sweeny, S.J. Shire, C.C. Hsu, Pharmaceutical Research, 15, no. 5 (1998), 768-775; M. T. Vidgren, P.A. Vidgren, T.P. Paronert, Int. J. Pharmaceutics, 35 (1987), 139-144; R.W. Niven, F.D. Lott, A.Y. 1p, J.M. Cribbs, Pharmaceutical Research, 11, no. 8 (1994), 1101-1109].

In addition to these examples, there are other production techniques recommended, above all, by pharmaceutical companies, especially based on the spray drying process, and which describe special formulations for inhalation powders.

In addition to the above requirements, it should generally be remembered that any change in the solid state of a drug, which, compared to less stable forms of the same drug, can improve its physical and chemical stability as well as its technical properties, offers a significant advantage.

Problem determination

The complex task of the proposed invention consists primarily in the preparation of a biologically available formulation for the highly effective CGRP antagonist BIBN4096. The formulation according to the invention for the treatment of acute pain conditions, which appear very suddenly in migraine, must show a rapid onset of action. This means that a rapid absorption of the active substance and a rapid increase in its amount in the plasma should be ensured.

Description of the invention

A faster establishment of action for the treatment of acute pain conditions, as well as a higher amount of the active substance BIBN4096 in the plasma in a short time, can be achieved, in addition to intravenous administration, best through the lungs as the organ for receiving the drug.

In the context of the proposed invention, it has surprisingly been found that BIBN4096 can be made sufficiently bioavailable in the form of the base of the active substance by inhalation. It has been shown that when the active substance is administered by inhalation in the form of round nanostructured microparticles, a biological availability of approx. 60% in relation to the fine fraction of the formulation (corresponding to the FPD determination according to USP 24 Suppl. 2000).

The formulation according to the invention does not require any addition of carrier materials.

The first object of the proposed invention is therefore an inhalation powder, which contains the active substance base 1-[H2-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl) -1-piperidinyl]-carbonyl]-D-tyrosyl]-1-lysyl]-4-(4-pyridinyl)-piperazine [BIBN4096] of formula (I) in the form of round nanostructured particles, which is characterized by

(a) the particles have a specific surface between 1 m2/g and 25 m2/g, preferably between 1 m2/g and 20 m2/g, especially preferably between 3 m2/g and 10 m2/g,

(b) the characteristic value of Q(5,8) is between 50% and 100% and

(c) parameter X50 is between 1 μm and 6 μm.

These microparticles are characterized by special physical and chemical properties, which lead to an improved pharmacological-pharmacokinetic effect when the substance is inhaled. The availability of the substance, both quantitatively in relation to the given amount of the active substance, and also in relation to the possible rapid achievement of a high amount in the plasma, is caused by the biochemical properties of the substance as well as the physicochemical properties. If a solid substance is administered, as in the case of inhalation powder, the parameter of absolute solubility in the environmental medium should be taken into account here, and also the rate of dissolution in the environmental medium as a function of the local concentration of the active substance and time.

For optimal inhalation administration, it must therefore be taken into account that the particles of the active substance form a finely divided coating on the surface of the lungs. That is why it is most important to change the active substance so that the inhaled microparticles have advantages in terms of their particle-particle interaction, as well as their dispersion, i.e. aerodynamic properties, which cause them to deposit quantitatively in the deeper area of the lungs on the one hand, and on the other hand to cover the largest possible lung surface. This is why the physico-chemical properties of microparticles for inhalation are of great importance for inhalation powder.

The particles produced by the process according to the invention have a high physical stability. In particular, when used as an inhalation powder, the properties of the particles allow obtaining a high proportion of small particles, which is technically determined, for example, by measuring with a cascade impactor (Andersen cascade impactor, according to USP 24, or Pharm. Eur. Suppl. 2000). According to this method, the proportion of particles that are smaller than 5 μm (aerodynamic) is usually greater than 15%, while in some cases the proportion of the fine fraction is greater than 50%. In addition to this key parameter, inhalation powder is characterized by the fact that he can further process with usual technical procedures. The thus produced powder is characterized by the physico-chemical parameter of particle size, measured for example by diffraction of laser beams, as well as the specific surface area, measured for example by B.E.T. by measuring in several points. For a characteristic value of Q(5,8), the particle size of the powder thus produced is usually between 50% and 100%, and the parameter X50 is between 1 μm and 6 μm. In addition, the particles produced by the above process have typical specific surface values between 1 m2/g and 25 m2/g, in the best case between 1 m2/g and 20 m2/g, and in a particularly favorable case between 3 m2/g and 10 m2 /Mr. Geometrically, the particles produced by the above process have a shape that can be described, depending on the experimental conditions, between the limits "sphere shape", "sphere shape with a hollow space, possibly with a hole", "sphere shape with convexity facing inwards", as well as in the form of a "collapsed hollow body". Seen with a scanning electron microscope, the surface of such particles is maximally nanostructured.

According to the invention, it was surprisingly found that BIBN4096 in the form of a free base can be changed morphologically by a spray drying process so that the thus produced powder can be filled directly into the first packaging means without further steps, above all without the necessary mixing with a larger carrier material, and from it can deliver for inhalation using a powder inhalation device.

In doing so, the production process can be conducted in such a way as to obtain particles of a suitable core size, usually between 0.1 and 10 μm, and these particles have such surface properties that they can be easily fluidized/dispersed.

Furthermore, it was found that the morphology of the particles, including the size of the particles, can be significantly and targeted influenced by the choice of process parameters and production parameters. At the same time, it is surprising that the powder of this substance is micronized by a "classical" jet milling process, which results in a similar spectrum of particle sizes, which, however, are morphologically significantly different from the particles produced according to this invention, as regards their surface properties and of particle-particle interaction. This can be seen by the fact that the quality parameter "Fine Particle Fraction of Delivered Dose" (eg according to the method for determining "Aerodynamic Particle Size Distribution" - USP 24 or Pharm. Eur. Suppl. 2000) improves by a factor of 10 or more. Since the carrier material can be omitted from the formulation at the same time, with a predetermined total amount of powder for application, the actual and absolute dose of the active substance available to the patient is improved by an even significantly higher factor.

The production process according to the invention is characterized by the fact that the active substance is dissolved in a suitable way, sprayed and dried in a spray tower. The principle of spray drying is that the solution or suspension of the product to be dried is divided into small droplets and dried with a hot stream of gas. The portion of the solid substance, which remains after the evaporation of the solvent, is separated from the gas stream by means of a separator acting on inertial force (eg a cyclone) and/or with a filter, and is collected. At the same time, the microparticles produced in this way are characterized by special values in terms of particle size, specific surface area and morphology.

Organic solvents, i.e. mixtures of organic and aqueous solvents, proved to be suitable solvents. An alcohol-water solvent system is primarily used, a solvent mixture consisting of ethanol/methanol/water as well as ethanol/propanol/water is particularly favorable, and a solvent mixture of ethanol and water is particularly favorable. At the same time, in the solvent mixtures, the molar proportion of water is used, which ranges from 0.1 times to 10 times the molar proportion of the alcohol components, preferably from 0.5 to 4 times the quantity.

Adjusting the concentration of the active substance primarily serves to make the procedure economical. In doing so, however, the limits for adjusting the concentration of the active substance are set, which are predetermined so that with a certain ratio between the size of the droplets and the concentration of the solid substance, the surface properties of the particles can be optimized. A concentration between 0.5 and 20 mass percent is usually chosen, preferably between 2 and 10 mass percent, and especially advantageously between 3 and 8 mass percent. Droplet size is a crucial parameter for obtaining inhalable particles. Depending on the nozzle used, the spray gas stream is selected in combination with the solution flow to achieve the desired droplet size. Since there is a combination of a large number of nozzle parameters - spray gas flow and solution flow - that lead to a favorable droplet size, it makes sense to define the process by the droplet size that must be selected for the process. It can be characterized with the characteristic X50 (mean value = particle size/droplet size, below which 50% of the amount of particles is located in relation to the volume distribution of individual particles/droplets) which must be in the range between 1.5 μm and 20 μm, preferably between 1.5 μm and 8 μm, as well as the characteristic Q(5,8) (which corresponds to the amount of particles that are below 5.8 μm in relation to the droplet volume distribution), which must be between 10% and 100%, preferably between 30% and 100%.

In technical terms, this is achieved by using suitable commercial nozzles that have these characteristics, e.g. single or multi-substance nozzles, which, depending on the nozzle parameters (e.g. rotation speed in the case of rotary atomization or connected atomization pressure and gas flow size for the resulting atomization, in the case of dual-substance nozzles), as well as the atomization ratio (volume flow of the "spray solution"). Apart from the special conditions, which must be maintained during the respective sputtering process, in order to obtain suitable droplets for the drying process, it has been shown that the surface properties of the particles can also be positively/targeted influenced by the choice of drying parameters. The decisive characteristic parameters, which enter the drying stage, are the inlet and outlet temperature of the drying gas, as well as the volume flow of the passed drying gas. It should be noted that droplets of suitable size are guided through the drying chamber so that the droplets and dried particles do not contact the wall of the spray tower or only touch it slightly. This is achieved by using a nozzle with a suitable spray cone, with a spray tower of suitable diameter and with the flow conditions in the apparatus. The outlet temperature for the procedure must be adjusted so that the powder has a sufficiently low content of residual solvent and thus sufficient chemical and physical stability. This is most advantageously achieved if the outlet temperature is kept in the region of the boiling point, i.e. slightly above it. Conversely, the inlet temperature of the drying gas must be selected so that, in combination with the "drying gas" volume flow parameter as well as the spray rate, drying takes place so carefully that particles with suitable surface properties are produced.

The second object of the invention is therefore a process for the production of the active substance based on BIBN4096 in the form of round nanostructured microparticles, which includes the following stages

(a) dissolving the active substance BIBN4096 in an organic solvent or in a mixture of organic-aqueous solvent to prepare a solution of the active substance with a concentration of the active substance between 0.5 and 20 wt. %, preferably between 2 and 10 wt. %, especially preferably between 3 and 8 wt. %,

(b) dispersing the solution of the active substance thus obtained in a conventional manner, so as to obtain a mist with a droplet size having a characteristic X50 in the range of 1.5 to 20 μm, preferably in the range of 1.5 to 8 μm, and Q(5 ,8) between 10 and 100%, preferably between 30 and 100%,

(c) drying of the thus obtained powder from spraying using a drying gas using the following parameters:

• inlet gas temperature for drying from 100°C to 350°C, preferably between 120°C and 250°C, and especially preferably between 130°C and 200°C,

• outlet gas temperature for drying from 40ºC to 120°C,

• volume flow of atomizing gas from 1 Nm3/h to 15 Nm3/h i

• drying gas volume flow from 15 Nm3/h to 1500 Nm3/h, preferably between 15 Nm3/h to 150 Nm3/h, and

(d) separating the dried solids fraction from the drying gas stream in a conventional manner.

The third object of the invention is the use of the active substance of the BIBN4096 base in the form of round nanostructured microparticles, which can be obtained by the process described above, for the production of inhalation powder.

The fourth object of the invention is an inhalable powder, which is characterized by the fact that round nanostructured particles can be obtained by the method described above according to the invention.

Experimental part

1) Measuring procedures

a) Determination of particle size by diffraction of laser beams (Frauenhofer diffraction)

Measurement procedure: To determine the particle size, the powder is placed in a laser diffraction spectrometer using a dispersing device. The mean value X50 refers to the particle size below which 50% of the particle quantity is located. The value Q(5,8) describes the percentage of particles with a size below 5.8 μm.

Measuring device: Laser Diffraction Spectrometer (HELOS), Sympatec company.

Software package: WINDOX version 3.3/REL 1 for examples 1 to 3 and version 4 for examples 4 to 6.

Dispersing device: RODOS/dispersing pressure: 3 bar.

Focal length: 100 mm [measuring range: 0.9..... 175 μm].

Value display mode: HRLD (V 3.3 Rel. 1).

b) Determination of the specific area

Measurement procedure: The specific surface area is determined by exposing the powder sample to a nitrogen atmosphere under different pressures. By cooling the sample, condensation of nitrogen molecules occurs on the surface of the particles. The amount of condensed nitrogen is determined through the pressure drop in the system, and the specific surface area of the sample is calculated through the surface consumption of nitrogen and the weighing of the sample.

Measuring device: Tri Star Multi Point BET, company Micromeritics.

Heating device: VacPrep 061, Micromeritics.

Heating time: approx. 12h/40°C

Analysis parameters

Sample container: 1/2 inch; with "filler rod";

analysis procedure: BET surface measurement in 16 points o.05 to 0.20 p/p0;

absolute pressure tolerance: 5.0 mm Hg;

relative pressure tolerance: 5.0%;

evacuation rate: 50.0 mm Hg/second;

evacuation threshold: 10.0 mm Hg;

duration of evacuation: 0.1 h;

empty volume: descent of the Dewar vessel, t: 0.5 h;

dwell time: 20 seconds;

minimum balance duration: 600 seconds;

absorbent: nitrogen.

c) Determination of droplet size using laser diffraction (according to Mie):

Measuring device: laser diffraction spectrometer (HELOS), Sympatec company.

Software package: WINDOX version 4.

Focal length: 100 mm [measuring range: 0.9,.... 175 μm] .

Measurement procedure: Determining the droplet size is done by removing the nozzle from the spray dryer and placing the spray in the upper third of the conical part of the spray nozzle in the middle of the laser beam. The measurement is performed at room temperature with water as a comparative agent, under otherwise equal conditions.

2) Examples

Example 1

Spray parameter suitable for alcohol solution BIBN4096 (modified BÜCHI spray dryer)

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Characterization of the solid particles obtained:

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Example 2

Spray parameter suitable for alcohol solution BIBN4096 (modified BÜCHI spray dryer)

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Characterization of the solid particles obtained:

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Example 3

Spray parameter suitable for alcohol solution BIBN4096 (modified BÜCHI spray dryer)

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Characterization of the solid particles obtained:

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Example 4

Spray parameter suitable for alcohol solution BIBN4096 (modified BÜCHI spray dryer)

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Characterization of the solid particles obtained

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Example 5

Spray parameter suitable for alcohol solution BIBN4096 (modified BÜCHI spray dryer)

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Characterization of the solid particles obtained:

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Example 6

Spray parameter suitable for alcohol solution BIBN4096 (modified BÜCHI spray dryer)

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Characterization of the solid particles obtained

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Short description of the pictures

Figures 1 to 6 show images of microparticles of the active substance of the base BIBN4096, which were produced by the process of spraying an alcoholic solution according to the invention.

Claims (12)

1. Inhalation powder, which as an active substance contains the base 1-[N2-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxo-quinazolin-3-yl)- 1-piperidinyl]carbonyl]-D-tyrosyl]-1-lysyl]-4-(4-pyridinyl)-piperazine [BIBN4096] of formula I [image] in the form of round nanostructured particles, indicated by that (a) the particles have a specific surface between 1 m2/g and 25 m2/g, (b) the characteristic value of Q(5,8) is between 50% and 100% and (c) parameter X50 is between 1 μm and 6 μm. 2. Inhalation powder according to claim 1, characterized in that the particles have a specific surface between 1 m2/g and 20 m2/g. 3. Inhalation powder according to claim 1, characterized in that the particles have a specific surface between 3 m2/g and 10 m2/g. 4. The process for the production of the active substance of the base BIBN4096 in the form of round nanostructured microparticles, characterized by the fact that it includes stages (a) dissolving the active substance BIBN4096 in an organic solvent or in a mixture of organic-aqueous solvent to prepare a solution of the active substance with a concentration of the active substance between 0.5 and 20 wt. %, (b) dispersing the solution of the active substance thus obtained in a conventional manner, so as to obtain a mist with a droplet size having a characteristic X50 in the range of 1.5 to 20 μm, preferably in the range of 1.5 to 8 μm, and Q(5 ,8) between 10 and 100%, preferably between 30 and 100%, (c) drying the thus obtained mist using a drying gas using the following parameters: • inlet gas temperature for drying from 100°C to 350°C, preferably between 120°C and 250°C, and especially preferably between 130°C and 200°C, • outlet gas temperature for drying from 40°C to 120°C, • volume flow of atomizing gas from 1 Nm3/h to 15 Nm3/h i • drying gas volume flow from 15 Nm3/h to 1500 Nm3/h, preferably from 15 Nm3/h to 150 Nm3/h, and (d) separating the dried solids fraction from the drying gas stream in a conventional manner. 5. The method according to claim 4, indicated by the fact that the solvent, which is used to dissolve the active substance, is an organic-aqueous solvent system, where the molar fraction of water is used from 0.1 times to 10 times the molar fraction of the alcohol component , preferably from 0.5 to 4 times the amount. 6. The method according to claim 4, indicated by the fact that the organic-aqueous solvent system consists of ethanol/methanol/water, where the molar fraction of water is used from 0.1 times to 10 times the molar fraction of the alcohol component, preferably from 0.5 to 4 times the amount. 7. The method according to claim 4, indicated by the fact that the organic-aqueous solvent system consists of ethanol/propanol/water, where the molar fraction of water is used from 0.1 times to 10 times the molar fraction of the alcohol component, preferably from 0.5 to 4 times the amount. 8. The method according to claim 4, indicated by the fact that the organic-aqueous solvent system consists of ethanol/water, where the mole fraction of water is used from 0.1 times to 10 times the amount of the mole fraction of the alcohol component, preferably from 0, 5 to 4 times the amount. 9. The method according to any of claims 4 to 8, characterized in that the active substance solution used for spray drying has a concentration of 2 to 10 wt. %. 10. The method according to any of claims 4 to 8, characterized in that the active substance solution used for spray drying has a concentration of 3 to 8 wt. %. 11. Use of the active substance based on BIBN4096 in the form of round nanostructured microparticles, obtained according to any of claims 4 to 10, characterized in that they are used for the production of inhalation powder. 12. Inhalation powder according to any claim 1 to 3, characterized in that round nanostructured particles can be obtained by the process according to any claim 4 to 10.